1-(2-carboxyphenyl)-5,7-dimethoxy-3,4-dihydrocarbostyril intermediates for acronycis

ABSTRACT

The total synthesis of acronycine and related compounds with readily available 1-(2-carboxyphenyl)-5,7-dialkoxy-3,4dihydrocarbostyrils is described, as are various classes of other intermediates useful in the synthesis.

United States Patent 91 Beck Apr. 17, 1973 1-(2-CARBOXYPHENYL)-5,7- [56]References Cited DIMETHOXY'34' UNITED STATES PATENTS DIHYDROCARBOSTYRILINTERMEDIATES FOR ACRONYCIS 3,117,959 1/1964 Dehnert ..260/28? R ['75]Inventor: James R. Beck, Indianapolis, Ind. THE PUBLICATIONS AssigneerEli Lilly and p y, Indianapolis, Beck et a1. Jour. Am. Chem. Soc. Vol.89, p. 3934 [22] plied: July 1971 Primary ExaminerD onald G. Daus [21Appl. No.: 128,527 Attorney-Everet F. Smith et a].

Related U-S- Application Data [62] Division of Ser. No. 653,667, Julyl7, 1967, Pat. No. The total Synthesis of acronycine and rela'tgd poundswith readily available l-( 2-carboxyphenyl)-5,7-dialkoxy-3,4-dihydrocarbostyrils is described, as [52] US. Cl...260/287 R are Various Classes of other intermediates useful in the 51'Int. Cl. ..C07d 33/00 synthesis [58] Field of Search ..260/287 R 1Claim, N0 Drawings 1 l-(2-CABOXYPI-IENYL)-5,7-DIMETHOXY-3,4-DIHYDROCARBOSTYRIL INTERMEDIATES FOR ACRONYCIS CROSS-REFERENCE TORELATED APPLICATION This application is a division of co-pendingapplication, Ser. No. 653,667, filed July 17, 1967 now US. Pat. No.3,624,087.

BACKGROUND OF THE INVENTION O OCHs A w o,

cinw In addition, Govindachari et al. isolated the related compounds,noracronycine, des-N-methylacronycine and des-N-methyl-noracronycine,from the root bark of Glycosmis pentaphylla. Finally, the synthesis ofacronycine from noracronycine was described in Aust. J. Scl. Res. 2A,622 (1949).

Recently, it was foundby Svoboda and co-workers [J. Pharm. Scif55, 758(1966) and Lloydia 29, 206

(1966)]that acronycine had an extremely powerful anti-tumor actionagainst transplanted tumors in mice, particularly against Shionoglcarcinoma, C4498 myelogenous leukemia, Mecca lymphosarcoma and 5563plasma cellmyeloma.

, SUMMARY This invention provides a method of synthesizing acronycinewhich comprises first cyclizing N-(B-halopropionyl)-3,S-di-lower-alkoxyaniline "to yield a5,7-di-lower-alkoxy-3,4-dihydrocarbostyril, reaction of which with ano-halobenzoic acidunder Ullman conditions yields al-(2-carboxyphenyl)-5,7-di-lower-alkoxy-3,4-dihydrocarbostyril.Treatment of the lattercornpound with a condensing agent such aspolyphosphoric.

acid yields a mixture of a 3-(l,3-dialkoxy-9-oxo-4- acridanyl) propionicacid and the corresponding inner lactam. Esterification of this mixturewith an alkanol yields a lower alkyl 3-(l,3-dialkoxy-9*oxo-4-acridanyl)propionate. This latter compound is nextselectively dealkylated to give a lower alkyl 3-(l-hydroxy-3-lower-alkoxy-9-oxo-4-acridanyl)propionate, alkylation of which with analkyl lithium orlower-alkyl Grignard reagent yields a1-hydroxy-3-lower-alkoxy-4-(3-hydroxy-3,3-di-lower-alkylpropyl))-9-oxoacridane. Treatment of thislatter compound with acid yields a 6-hydr0xy-3,3-di-lower-alkyl-2,3-dihydro-7( 12H) l H-phrano-[2,3-celacridanone.

In the above reaction when there is no substituent present in theo-halobenzoic acid and where the alkylating agent is methyllithium ormethylmagnesium bromide, the resulting compound isN-desmethylnordihydroacronycine. N-methylation ofN-desmethylnordihydroacronycine followed by selective dehydrogenationusing dichlorodicyanoquinone (DDQ) yields noracronycine directly.O-alkylation of noracronycine yields acronycine. The above synthesis canbe. visualized in Reaction Scheme I which follows:

REACTION SCHEME I l dualkylatc alkylation alk =I'I(acronyclnc) In theabove reaction scheme, X and X can be chlorine, bromine or iodine andalk is a lower-alkyl group having from 1 to 4 carbon atoms, eitherstraight chained or branched chained, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl and the like: R can be hydrogen,halogen, nitro, trifluoromethyl, alk, or Oalk; R is hydrogen, methyl,ethyl, benzyl; and R" is methyl or ethyl.

As previously mentioned the first step of our novel multi-step synthesisof acronycine involves the cyclization of anN-(B-halopropinyl)-3,S-di-lower-alkoxyaniline (I) to a 5,7-di-lower-alkoxy-3,4-dihydrocarbostyril (II). The cyclization iscarried out by the fusion of (I) with a mild, essentially anhydrous,Friedel-Crafts catalyst such as zinc chloride, zinc bromide, stannouschloride, antimony trichloride and the like, optionally in the presenceof an alkali metal halide; The fusion of (I) in the presence of one ofthe aforementioned heavy metal catalysts is carried out at a temperatureof about 50C. to about 250C., no solvent being required. In carrying outthe cyclization of (I), we prefer to use zinc chloride in a relativelyanhydrous state in combination with an alkali metal halide, such assodium chloride, at a temperature of about 150C. although higher orlower temperatures are fully operative. Addition of two parts of sodiumchloride to one part of the zinc salt has an advantageous effect on theyield of (II).

In the second step, the 3,4-dihydrocarbostyril (II) is reacted with ano-halobenzoic acid (Ill) in the presence of cuprous iodide orothercuprous salt to yield the l-(2-carboxyphenyl)-3,4-dihydrocarbostyril (IV). The

reaction conditions are typically those used in the Ullmann reaction.The reaction is carried out in an inert solvent, such as nitrobenzene,in the presence of a hydrogen halide acceptor, such as, potassiumcarbonate, sodium carbonate and the like at a temperature of about C. toabout 250C. We prefer to carry out the reaction of (II) with (III) whereX is iodo in the presence of cuprous iodide in nitrobenzene at atemperature of about C. for 24 hours.

The l-( 2-carboxyphenyl)-3 ,4-dihydrocarbostyril (IV) produced in theabove reaction is then cyclized by treatment with polyphosphoric acid orother equivalent condensing agent at a temperature of about 50C. toabout 150C. to yield a mixture consisting of al,3-dilower-alkoxy-9-oxo-4-acridanylpropionic acid (VI) and thecorresponding inner lactam, 2,3-dihydro-4,6- di-lower-alkoxylH,7H-pyrido-[ 3 ,2, l -d'e]acridine-l ,7- dione (V) where alk and R areas defined above. This cyclization is preferably carried out at atemperature of about 90C., though higher or lower reaction temperaturesare fully operative.

The mixture comprising (V) and (VI) is next treated with l. N methanolicor ethanolic hydrogen chloride at reflux temperature to yield theoptionally substituted methyl or ethyl 9-oxo-4-acridanyl-propionate(VII), where R, R" and alk are as defined above. During this reaction,the 2,3-dihydro-4,6-di-lower-alkoxy-lH,7H- .pyrido-[3,2,l-de]acridine-l,7-dione (V) component of the above mixture is converted to (VII) by analcoholysis reaction, and the acridanyl-propionic acid (VI) component ofthe mixture is concurrently converted to (VII) by esterification. Thus,the separation of the mixture of (V) and (VI) is obviated by this onestep methanolysisesterification reaction.

, The 9-oxo-4-acridanylpropionate (VII) is then selectively dealkylatedto yield a 1-hydroxy-3-methoxy-9- oxo-4-acridanyl-propionate (VIII),based on the procedure of F. M. Dean et al., Tetrahedron Letters,4153-4159 (1966), which procedure utilizes boron trichloride in an inertsolvent as the dealkylating agent. Alternatively, this selectivedealkylation of the l-alkoxy group of (VII) to obtain (VIII) has beencarried out with a Grignard reagent in an ether-pyridine solvent systemat a temperature of about 60C. In this alternate procedure, thepreferred Grignard reagent, selected from among the lower alkylmagnesiumbromides or iodides-for example methylmagnesium iodide in ether-4s firstmixed with pyridine. Next a pyridine solution of (VII) is added. Thereaction mixture is then heated for about 4 hours at a temperature ofabout 60C. to yield (VIII). We prefer, however, to carry outtheselective demethylation of (VII) by the aforementioned procedurebased upon that of F. M. Dean et al., loc. cit. According to thisprocedure, (VII) is dissolved in methylene chloride and the solutiontreated with excess gaseous boron trichloride at a temperature of about0C. The reaction is carried to completion by allowing the mixture toremain at ambient temperature for 30 minutes. Excellent yields of thel-hydroxy-3-alkoxy-9-oxo-4-acridanylpropionate (VIII) are thus obtained.

The monohydroxy compound (VIII) is next reacted with a loweralkyllithium where lower alkyl is the same as defined above, in anethereal solvent such as diethyl ether, tetrahydrofuran or diethyleneglycol dimethyl ether, to yield a tertiary carbinol (IX). In thisreaction, the alkyllithium converts the propionate ester group to atertiary alcohol. The reaction is carried out at a temperature in therange 70C. to 0C. in an inert atmosphere of a gas such as nitrogen. Weprefer to carry out the preparation of (IX) in the solventtetrahydrofuran at a temperature of about -20C. with a reaction time ofabout 30 minutes to obtain maximal yields of the tertiary carbinol.

Upon treatment of the tertiary carbinol (IX) with 48 percent hydrobromicacid in glacial acetic acid at or near reflux temperature cyclizationoccurs involving the 3-alkoxy substituent and the tertiary hydroxylgroup of (IX) to yield the 3,3-di-lower-alkyl-2,3-dihydro-7(12I-I)-lH-pyrano[2,3-c]acridinone (X). Preferably, however,the above cyclization is carried out by fusing (IX) with pyridinehydrochloride at a temperature of about 200C. The reaction is usuallycomplete after about four hours. (X) is obtained in a purified state bycolumn chromatography over silica gel or similar material in abenzene-ethyl acetate solvent combination. Alternatively, we find itadvantageous in carrying out our synthesis to convert (X) in the crudestate to the more easily isolatable (Xl) by the N-alkylation of (X) witha methyl halide, an ethyl halide or a benzyl halide in refluxing acetonein the presence of potassium carbonate. The above cyclization reactionwhereby an alkoxy group undergoes cleavage, followed by intramolecularcyclization with a tertiary carbinol, is unique and indeed is a key stepin the total synthesis of acronycine and related compounds. The productof the above alkylation (X) where R is H is classified as aN-desmethyln0rdihydroacronycine but when R is other than hydrogen,

the compound is classified as a dihydronoracronycinef Treatment ofeither the nonnal or the N-desmethyl derivative with a quinone having ahigh standard oxidation potential (E), preferably in the neighborhood of1.0 volt in an inert solvent, yields a 6-hydroxy-3,3-dilower-alkyl-l,2-dihydro-pyrano-[ 2 ,3 -ce ]acridinone (XIII). We prefer to carry outthis dehydrogenation with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) inrefluxing toluene over a 1-3 hour period. This unique method for theintroduction of the carbon to carbon double bond in the dihydropyranylring of (X) or (XI) affords surprisingly high yields.

In carrying out the series of reactions depicted in Reaction Scheme I,where R is H, R and alk are methyl, dihydronoracronycine was obtained(XI). Oxidation of dihydronoracronycine with DDQ as described aboveafforded noracronycine identical in physical and chemical properties tothe natural noracronycine reported by R. D. Brown, L. J. 1 3mmmond, F.N. Lahey and W. C. Thomas, Australian J. Sci. Research A2, 423 (1949).Methylation of noracronycine by the method of R. D. Borwn et. al., loc.cit. yielded acronycine.

The above synthetic procedure when carried out with compounds in whichalk and R are methyl and R is hydrogen yields acronycine which, as hasbeen previously stated, has been found to be extremely useful in thetreatment of experimental tumors in mice and is a potential addition tothe armamentarium of antineoplastic drugs. The process of this inventionis also useful for preparing compounds related to acronycine in whichalk, R and R are other than as specified as acronycine. These compounds,as well as compounds related to noracronycine [(XIII) where R' isotherthan hydrogen and alk is methyl] have an effect on the cen: tral nervoussystem which is generally a stimulating ac tion, although certain of thecompounds have sedative effects. Compounds corresponding to formulas II,IV, V, VI, VII, VIII, IX and X all represent novelstructures and are alluseful as intermediates for the preparation of acronycine and relatedcompounds as represented by XV.

Further aspects and equivalents of the present invention will becomeobvious to one skilled in the art. The following examples further definethe present invention but are not intended in any way to limit the scopeof the invention.

EXAMPLE I 5 ,7-Dimethoxy-3 ,4-dihydrocarbostyril One hundred and thirtygrams of 3,5-dimethoxy-N- (B-bromo-propionyl) aniline and g. of zincchloride (previously dried for 2 hoursat C.) were fused at 150C. for 30minutes. The reaction mixture'was allowed to cool to room temperatureand the 5,7- dimethoxy-3,4-dihydrocarb0styril formed in the abovereaction was extracted therefrom with 400 ml. of ethyl acetate. Theextract was washed successively with 400 ml. of 3 N hydrochloric acid,with a saturated solution of sodium bicarbonate and with a saturatedsolution of sodium chloride. The extract was separated and dried,

and the solvent removed therefrom to yield 17 g. of5,7-dimethoxy-3,4-dihydrocarbostyril melting at about 192-194C. afterrecrystallization from methyl a1- cohol.

Analysis-Calculated: C, 63.75; H, 6.32; N, 6.76 Found: C, 63.83; H,6.64; N, 6.76

EXAMPLE 2 5,7-Dimethoxy-3,4-dihydrocarbostyri1 (Zinc chloride-sodiumchloride method) One hundred and forty grams of 3,5-dimethoxy-N-(B-bromopropionyl) aniline were added rapidly to a mixture, previouslydried at 155C. for 2.5 hours, consisting of 70 g. of zinc chloride and140 g. of sodium chloride at a temperature of about 155C. The reactionmixture was maintained at a temperature of about 155C. for 20 minutes,cooled to room temperature, and 5,7-dimethoxy-3,4-dihydrocarbostyrilformed in the above reaction was extracted therefrom with 500 ml. ofethyl acetate. The extract was washed successively with 400 ml. of 3 Nhydrochloric acid, water, a saturated solution of sodium bicarbonate,and a saturated solution of sodium chloride. The extract was separatedand dried and the solvent evaporated therefrom in vacuo. The resultingresidue yielded 16.9 g. of 5,7-dimethoxy-3,4-dihydrocarbostyril meltingat about l92-194C. after recrystallization from methanol. The motherliquor was evaporated in vacuo to yield 100 g. of an oil consisting ofpartially demethylated product. The oil was treated with a mixture of300 ml. of methyl iodide and 240 g. of potassium carbonate in l-liter ofacetone at reflux temperature for 72 hours. The reaction mixture wascooled, filtered, and the solvent evaporated in vacuo. An additional11.7 g. of 5,7- dimethoxy-3,4-dihydrocarbostyril melting at about l95l96C. after recrystallization from methanol were obtained from theresidue.

Analysis-Calculated: C, 63.75; H, 6.32; N, 6.76 Found: C, 63.83;H,6.64;N, 6.76

EXAMPLE 3 l-( 2-Carboxypheny1)-5 ,7-dimethoxy-3 ,4-dihydrocarbostyrilEight grams of 5,7-dimethoxy-3,4-dihydrocarbostyril and 19.8 g. of2-iodobenzoic acid were reacted together in the presence of 0.5 g. ofcupious iodide, 0.2 g. of cupric acetate monohydrate, 16 g. of potassiumcarbonate and 175 ml. of nitrobenzene. The reaction mixture wasmaintained at a temperature of about 150C. for 24 hours with continualstirring, and was then steam distilled to remove the nitrobenzene. Theaqueous mixture was filtered and acidified.1-(2-Carboxyphenyl)-5,7-dimethoxy-3,4-dihydrocarbostyril, formed in theabove reaction, was extracted therefrom with 400 ml. of ethyl acetate.The organic extract was washed with a saturated solution of sodiumchloride which was discarded. The carbostyril was extracted from theorganic layer with a saturated aqueous solution of sodium bicarbonate.The sodium bicarbonate extract was acidified and the productre-extracted with ethyl acetate. The ethyl acetate extract was dried,and the ethyl acetate removed therefrom by evaporation in vacuo. Threegrams of l-(2-carboxyphenyl)-5,7- dimethoxy-3,4-dihydrocarbostyril wereobtained from the resulting residue melting at about 223-225C.

after recrystallization from methyl alcohol.

Analysis--Calculated: C, 66.05; H, 5.24; N, 4.28

Found:C,65.83;l-l,5.37;N,4.22

EXAMPLE 4 Methyl 3-(1,3-dimethoxy-9-oxo-4-acridanyl)- propionate Fourgrams of 1-(2-carboxyphenyl)-5,7-dimethoxy- 3,4-dihydrocarbostyrilprepared as in Example 3, and ml. of polyphosphoric acid were mixedtogether and the mixture heated at about 100C. for 1.5 hours. Thereaction mixture was poured over 400 g. of crushed ice, yielding a solidprecipitate which was filtered and dried by azeotropic distillation. Thedried precipitate was dissolved in 100 ml. of 1 N methanolic hydrogenchloride and the solution refluxed for 2.5 hours. The solvent wasremoved therefrom by evaporation in vacuo to yield 3.7 g. of a residueconsisting essentially of methyl3-(1,3-dimethoxy-9-oxo-4-acridanyl)-propionate. Suspension of theresidue in 400 ml. of a saturated sodium bicarbonate solution, followedby separation and recrystallization of the thus obtained product, gavepurified methyl 3-( 1 ,3-dimethoxy-9-oxo- 4-acridanyl)-propionatemelting at about 244-2 45C.

Analysis--Calculated: C, 66.85; H, 5.61; N, 4.10 Found: C, 66.81; H,5.64; N, 4.07

EXAMPLE 5 Methyl 3-( 1-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionateFour grams of methyl 3-(1,3-dimethoxy-9-oxo-4- acridanyl)-propionate,prepared as in Example 4, were dissolved in 300 ml. of methylenechloride and the solution treated with an excess of gaseous borontrichloride at a temperature of 5C. The reaction mixture was thenallowed to remain at room temperature for 30 minutes after which time300 ml. of water were added. The methylene chloride layer containingmethyl 3-( l-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionate formed inthe above reaction was separated and washed successively with 300 ml.water, 300 ml. of a saturated solution of sodium chloride. The washedmethylene chloride layer was dried and the solvent evaporated therefromyielding as a residue 3 g. of methyl3-(1-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionate melting at about194195C. after recrystallization from a chloroform-ethyl alcohol solventmixture.

Analysis-Calculated: C, 66.05; H, 5.24; N, 4.28 Found: C, 65.91; H,5.67; N, 3.94

EXAMPLE 6 Methyl 3-( l-hydroxy-3-methoxy-9-oxo-4-acridanyl)- propionate(Grignard method) To an ethereal solution of methylmagnesium iodideprepared in the usual manner from 200 mg. of magnesium and 0.3 ml. ofmethyl iodide, 10 ml. of dry pyridine were carefully added followed bymg. of methyl 3- (1,3-dimethoxy-9-oxo-4-acridanyl) propionate dissolvedin 15 ml. of pyridine. The reaction mixture was heated at a temperatureof about 50C. to about 60C.

for 20 hours and then poured over an ice-water mixture. The methyl3-(l-hydroxy-3-methoxy-9-oxo-4- acridanyl)-propionate formed in theabove reaction was extracted into chloroform, and the extract separatedand washed with a saturated solution of ammonium chloride. The organiclayer was then dried and the solvent evaporated therefrom in vacuo.144.2 Milligrams of methyl 3-(l-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate were obtained, melting at about l94l95C. afterrecrystallization from aqueous methanol.

EXAMPLE 7 l-Hydroxy-4-( 3-hydroxy-3-methylbutyl)-3 -methoxy-9-acridanone Six hundred fifty milligrams of methyl 3-( l-hydroxy-3-methoxy-9-oxo-4-acridanyl)-propionate, prepared as in Example 5, weredissolved in 50 ml. of tetrahydrofuran and reacted with ml. of a 1.7molar solution of methyllithium in diethyl ether at a temperature of l9C. The above reaction was carried out under nitrogen with continualstirring. After about 30 minutes, the reaction mixture was decomposedwith 100 ml. of 3 N hydrochloric acid and the l-hydroxy-4-(3-hydroxy-3-methylbutyl)-3-methoxy-9-acridanone formed in the above reaction wasextracted therefrom with 200 ml. of ethyl acetate. The extract waswashed successively with 200 ml. of a saturated solution of sodiumchloride, 200 ml. of a saturated solution of sodium carbonate and againwith a saturated solution of sodium chloride. The extract was dried andthe solvent evaporated therefrom. Six hundred and eighty-threemilligrams of l-hydroxy-4-( 3-hydroxy-3-methyl-butyl)-3-methoxy-9-oxoacridanone were obtained, melting at about 2 l 3-2l4 C. afterrecrystallization from ethyl acetate.

Analysis--Calculated: C, 69.70; H, 6.47; N, 4.28Found:C,69.4I;H,6.44;N,4.27

EXAMPLE 8 6-l-lydroxy-3,3-dimethyl-2,3-dihydro-7( 1 2H)-1H-pyrano[2,3-c]-acridinone Nine hundred eighty-five milligrams ofl-hydroxy-4- (3-hydroxy-3-methylbutyl)-3-methoxy-9-acridanone, preparedas in Example 7, were heated with 25 g. of pyridine hydrochloride at atemperature of 190 to 1959C. for 3 hours. The product of the reaction,6- hydroxy-3,3-dimethyl-2,3-dihydro-7( 12H)-1H- pyrano[2,3-c]acridinone, crystallized from the reaction mixture on the addition of200 ml. of water and was collected by filtration. The compound waspurified by chromatography, using a 5:1 benzene-ethyl acetate eluantover a column packed with 60 g. of silica gel. Thirty-five fractions of22 ml. each were collected at a flow rate of 88 ml. per hour. Fractions15 to 29 were combined and evaporated in vacuo, and the solid residuerecrystallized from a chloroform-ethanol sol vent mixture to yield 84mg. of purified 6-hydroxy-3,3-dimethyl-2,3-dihydro-7(12H)-lH-pyrano[2,3-c] acridinone melting at about27 3-274 C.

Analysis--Calculated: C, 73.20; H, 5.80; N, 4.74 Found: C, 73.38; H,5.65; N, 4.56

EXAMPLE 9 Nordihydroacronycine Forty-seven milligrams of6-hydroxy-3,3-dimethyl- 2,3-dihydro-7( l2H)-ll-l-pyrano[2,3-c]acridinone,

prepared as in Example 8, were dissolved in 50 ml. of acetone andreacted with 5 ml. of methyl iodide at reflux temperature for 5 hours inthe presence of 4 g. of potassium carbonate. The reaction mixture wasfiltered and then diluted with ml. of water. The acetone was removed byevaporation and nordihydroacronycine, formed in the above reaction, wasextracted from the aqueous layer with 100 ml. of ethyl acetate. Theextract was washed with 100 ml. of a satu rated solution of sodiumchloride, dried, and the ethyl acetate removed therefrom by evaporationin vacuo. 19.7 Milligrams of nordihydroacronycine were obtained, meltingat about 205-2ll2C. after recrystallization from chloroform-ethanol.

Analysis-Calculated: C, 73.77; H, 6.19; N, 4.53 Found: C, 73.61; H, 6.1l;N, 4.53

EXAMPLE 1 0 Noracronycine 309.4 Milligrams of nordihydroacronycine,prepared as in Example 9, and 249.7 mg. of 2,3dich1oro-5,5-dicyanoquinone were reacted in ml. of toluene at reflux temperature for1.5 hours. The reaction mixture was cooled to room temperature, anddiluted with 125 ml. of ethyl acetate. The diluted reaction mixture,after being washed successively with 250 ml. of a 5 percent solution ofsodium hydroxide and with 250 ml. of a saturated solution of sodiumchloride, was dried and the solvent evaporated in vacuo to yield 300 mg.of a solid residue containing noracronycine. The noracronycine waspurified by chromatography using a 30:1 benzene-ethyl acetate eluant,over a column packed with 200 g. of silicagel. One hundered and fortyfractions were collected of 15 ml. each. Fractions 84 to 103 werecombined and evaporated in vacuo to yield 144 mg. of noracronycinemelting at about 200 to 200.5C. after recrystallization from ethylacetate.

EXAMPLE 11 6-Hydroxy-3 ,3-diethyl-l0-nitro-2,3-dihydro-7(12H)-lH'pyrano[2,3-c]-acridinone Following the procedure of Example 1,3,5-di-npropoxy-n fl-chloropropionylaniline can be fused in the presenceof stannous chloride and sodium chloride to yield 5 ,7-di-n-propoxy-3,4-dihydrocarbostyril. Reaction of this compound with4-nitr'o-2-iodobenzoic acid under Ullmann conditions yieldsl-(2-carboxy-5- nitrophenyl )-5 ,7-di-n-propoxy-3 ,4-dihydrocarbostyril.Treatment of this latter compound with polyphosphoric acid followed byesterificatiion of the resulting product with ethanolic hydrogenchloride gives ethyl 3- l ,3-di-n-propoxy-6-nitro-9-oxo-4-acridanyl)'propionate, selective de-etherification of which yields thecorresponding l-hydroxy derivative. Reaction of this latter compoundwith ethyllithium gives l-hydrox'y-4-(3-hydroxy-3-ethylpentyl)-3-n-propoxy-6-nitro-9- acridanone treatmentof which with pyridine hydrogen chloride yields 6-hydroxy-3,3-diethyl-l0nitro-2,3- dihydro-7( l2H)-lH-pyrano[2,3-clacridinone.

Following the same procedure, but using an appropriately substitutedo-halobcnzoic acid and the proper alkylating agent, either alkyl lithiumor Grignard reagent, the following compounds can be prepared:

6-hydroxy-3,3-di-n-propyll0-cIhloro-2,3-dihydro-7( 3 5 UNITED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5,728,550 Dated April17, 1975 Inventor(s) J mes R Beck It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

In the lth line of the title on the cover page, "ACROYYCIS should read--ACRONYCINE-- In column 1, line 5, "ACRONYCIS" should read-ACRONYCINE-.

In column 1, line 16, "(l9h9)]l966" should read 9 +9)]. In 1966.

In Column 1, line 18, "Covindachari" should read -Govindachari--.

In column 1, line 21, "OOCH should be deleted.

In column 1', line 57, "J. Sol. Res." should read -J- Sci. Res.-'-.

In column 5, that portion of the structural Formula on the lower leftdepicted as follows:

In column 5, line #2, the colon after "like" should be replaced with asemicolon.

L In column 5, line "methanolysisesterification" should read as twowords as follows -methanolysis esterificatio 7 Certificate of CorrectionPage Two In column 6,, line 27, "Borwn" should read --Brown-'-.

In column line 68, "-7 should read -7- y In column ll, lines 1, 5, and7, "12H" should read --(l2H)--- In column ll, lines 2 and 6, "-T("should read -T- Signed a d ealed this 17th day of September 1974,

(.SEAL) Attest:

MCCOY M. GIBSONIVJR. c. MARSHALL DNN Attesting Officer Commissioner ofPatents

